The 20-year-old Italian did all he could to put the championship out of reach of his rivals in Texas on Sunday (Monday AEDT) but Ferrari's Lewis Hamilton and Mercedes teammate George Russell did just enough to delay the inevitable with fourth and eighth respectively.
Antonelli now needs to score only two points -- a ninth place -- in Mexico City to be sure of the title.
Ferrari's Charles Leclerc finished second, 13.078 seconds behind, at Austin's Circuit of the Americas with Red Bull's Max Verstappen third and helped by a late virtual safety car that slowed a chasing Hamilton who finished one second down the road.
Australia's Oscar Piastri finished seventh.
The dominant win from pole position on a one-stop strategy was Antonelli's ninth of the season and he now leads Russell by 123 points, and Hamilton by 124 with a maximum 125 remaining to be won and that reducing to 100 after Mexico.
"It was the result we needed and the whole team deserve it so much," Antonelli said.
"I know we're very close. We try to finish on a high and hopefully we can clinch it very soon".
McLaren's reigning champion Lando Norris finished fifth with Red Bull's Isack Hadjar sixth, and ahead of McLaren's Piastri.
Liam Lawson was ninth for Racing Bulls and Pierre Gasly took the final point for Alpine.
Antonelli made a flying getaway and was 2.3 seconds clear at the end of the opening lap while the Ferrari pair took the fight to slow-starting Verstappen for second place.
Leclerc went ahead, before being passed again by the Red Bull, and nearly made contact with Hamilton after the uphill scramble off the grid.
The virtual safety car was briefly deployed on lap two to allow marshals to clear debris and Russell was handed a five second penalty for gaining an advantage on Piastri on the opening lap at Turn 13.
"I was on the inside, he was overtaking on the outside, that's his risk," Russell said over the radio before the punishment.
Haas's Ollie Bearman also collected a 10 second penalty for causing a collision with Gasly and retired at the half-distance.
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